Synthesis and Evaluation of 11C-Labeled Triazolones as Probes for Imaging Fatty Acid Synthase Expression by Positron Emission Tomography.

James M Kelly,Wenchao Qu,Ethan J Linstad,Banafshe Samani,Nicole N Waterhouse,Stephen G Dimagno,Thomas M Jeitner,Clarence Williams,Anastasia Nikolopoulou,Alejandro Amor-Coarasa,John W Babich

doi:10.3390/molecules27051552

Abstract

Cancer cells require lipids to fulfill energetic, proliferative, and signaling requirements. Even though these cells can take up exogenous fatty acids, the majority exhibit a dependency on de novo fatty acid synthesis. Fatty acid synthase (FASN) is the rate-limiting enzyme in this process. Expression and activity of FASN is elevated in multiple cancers, where it correlates with disease progression and poor prognosis. These observations have sparked interest in developing methods of detecting FASN expression in vivo. One promising approach is the imaging of radiolabeled molecular probes targeting FASN by positron emission tomography (PET). However, although [11C]acetate uptake by prostate cancer cells correlates with FASN expression, no FASN-specific PET probes currently exist. Our aim was to synthesize and evaluate a series of small molecule triazolones based on GSK2194069, an FASN inhibitor with IC50 = 7.7 ± 4.1 nM, for PET imaging of FASN expression. These triazolones were labeled with carbon-11 in good yield and excellent radiochemical purity, and binding to FASN-positive LNCaP cells was significantly higher than FASN-negative PC3 cells. Despite these promising characteristics, however, these molecules exhibited poor in vivo pharmacokinetics and were predominantly retained in lymph nodes and the hepatobiliary system. Future studies will seek to identify structural modifications that improve tumor targeting while maintaining the excretion profile of these first-generation 11C-methyltriazolones.

Highlights

IntroductionFatty acids support a number of essential processes in cancer, including proliferation, energy, oncogenic signaling pathways, and resistance to therapy [1,3]
Increased lipogenesis is a phenotypic hallmark of many cancer cells [1,2]
Expression and activity of Fatty acid synthase (FASN) is elevated in multiple cancers [11–15], where it correlates with disease progression and poor prognosis [13,16,17]

Summary

Introduction

Fatty acids support a number of essential processes in cancer, including proliferation, energy, oncogenic signaling pathways, and resistance to therapy [1,3]. The fatty acid pool in cancer cells is fed by both de novo fatty acid synthesis and the uptake of exogenous fatty acids [4]. The majority of cancer cells overexpress lipogenic enzymes, including fatty acid synthase (E.C. 2.3.1.85; FASN) and exhibit a dependency on de novo fatty acid synthesis [5]. FASN synthesizes palmitate from acetyl-CoA and malonyl-CoA, using NADPH as a reducing equivalent [2], and is the rate-limiting enzyme of de novo fatty acid synthesis [6]. The products of de novo fatty acid synthesis in cancer cells are predominantly esterified to phospholipid aggregates that participate in signal transduction, intracellular trafficking, and cell migration [7]. Expression and activity of FASN is elevated in multiple cancers [11–15], where it correlates with disease progression and poor prognosis [13,16,17]

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